Solid-state mechanochemical cross-coupling of insoluble substrates into insoluble products by removable solubilizing silyl groups: uniform synthesis of nonsubstituted linear oligothiophenes

Conventional solution-based organic reactions that involve insoluble substrates are challenging and inefficient. Furthermore, even if the reaction is successful, the corresponding products are insoluble in most cases, making their isolation and subsequent transformations difficult. Hence, the conversion of insoluble compounds into insoluble products remains a challenge in practical synthetic chemistry. In this study, we showcase a potential solution to address these solubility issues by combining a mechanochemical cross-coupling approach with removable solubilizing silyl groups. Our strategy involves solid-state Suzuki–Miyaura cross-coupling reactions between organoboron nucleophiles bearing a silyl group with long alkyl chains and insoluble polyaromatic halides. The silyl group on the nucleophile can act as a solubilizing group that enables product isolation via silica gel column chromatography and can be easily removed by the addition of fluoride anions to form the desired insoluble coupling products with sufficient purity. Furthermore, we demonstrate that after aromatic electrophilic bromination of the desilylated products, sequential solid-state cross-coupling of the obtained insoluble brominated substrates, followed by desilylation, afforded further π-extended functional molecules. Using this conceptually new protocol, we achieved the first uniform synthesis of the longest nonsubstituted linear insoluble 9-mer oligothiophene.


Chemicals and instrumentation
Materials were obtained from commercial suppliers and used as received. Solvents were also purchased from commercial suppliers and further dried over molecular sieves (MS 4A). All mechanochemical reactions were carried out using grinding vessels in a Retsch MM400 mill ( Figure   S1). Both jars (1.5 mL and 5.0 ml) and balls (5 mm, 10 mm) are made of stainless (SUS400B and SUS420J2, respectively) ( Figure S2). The heat gun Takagi HG-1450B with a temperature control function was used for high-temperature ball-milling reactions ( Figure S3). NMR spectra were recorded on JEOL JNM-EC X400P and JNM-ECS400 spectrometers ( 1 H: 392 or 396 or 399 or 401 MHz, 13 C: 99 or 100 MHz). Tetramethylsilane ( 1 H), CDCl 3 ( 13 C) were employed as external standards, respectively. Multiplicity was recorded as follows: s = singlet, brs = broad singlet, d = doublet, t = triplet, q = quartet, quint = quintet, sept = septet, o = octet, m = multiplet. 1,1,2,2-Tetrachloroethane was used as an internal standard to determine NMR yields. High-resolution mass spectra were recorded at the Global Facility Center, Hokkaido University, and GC-MS & NMR Laboratory, Research Faculty of Agriculture, Hokkaido University. Recycle preparative gel permeation chromatography (GPC) was conducted with a JAI LaboACE LC-5060 using CHCl 3 as an eluent with JAIGEL-1H. Absorption spectra were recorded on a Hitachi U-2910 spectrometer. Emission spectra were recorded on a Hitachi F-7000 spectrometer.

Preparation of tris(3,5,5-trimethylhexyl)silane.
In a vacuum dried 50 mL two-necked round bottomed flask, magnesium (130.8 mg, 5.4 mmol) and a piece of iodine crystal were added to 10 mL anhydrous THF under a nitrogen atmosphere. 5,4.8 mmol) was added over 30 min, and the mixture was warmed up to 50 °C. Then, the mixture was stirred for 2 h to yield the Grignard reagent. The prepared Grignard reagent was transferred into the other vacuum dried 100 mL two-necked round-bottomed flask.
Trichlorosilane (121.0 mg, 0.89 mmol) was added slowly to a solution of the Grignard reagent at 0 °C, and then the mixture was then warmed to room temperature. After stirring for 14 h, the resulting suspension was quenched by the addition of saturated NH 4 Cl aqueous solution. The mixture was extracted with Et 2 O three times and dried over Mg 2 SO 4 . After filtration, the solvents were removed using a rotary evaporator. The residue was purified by silica-gel column chromatography (hexane only) and recycling preparative GPC to give the corresponding silane (353.6 mg, 0.86 mmol, 96%) as a colorless oil. 1

Preparation of tridodecylsilane.
In a vacuum dried 50 mL two-necked round-bottomed flask, magnesium (278.7 mg, 11.5 mmol) and a piece of iodine crystal were added to 11 mL anhydrous THF under a nitrogen atmosphere. 1-Bromododecane (2.72 g, 10.9 mmol) was added over 30 min, and the mixture was warmed up to 50 °C.
Example procedure for C-H silylation.
The reaction was performed according to the literature procedure. [Ir(cod)(OMe) 2 ] (16.5 mg, 0.025 mmol) and 4,4'-di-tert-butyl-2,2'-bipyridyl (dtbpy) (13.9 mg, 0.05 mmol) were placed in an oven-dried reaction vial. After the vial was sealed with a screw cap containing a Teflon-coated rubber septum, the vial was connected to a vacuum/nitrogen manifold through a needle. It was evacuated and then backfilled with nitrogen. This cycle was repeated three times. 1,4-Dioxane (0.2 mL), 2-norbornene (94.7 mg, 1.0 mmol), and trioctylsilane (251.3 mg, 0.68 mmol) were added in the vial at room temperature. The resulting mixture was allowed to warm at 100 ℃ and stirred for 5 h. After the reaction, the mixture was passed through a short silica gel column eluting with Et 2 O.
, Figure S5. The set-up procedure for the high-temperature solid-state cross-coupling. Disilylated novithiophene (7). 7 was synthesized from two different pathways, as described in the main text. Disilylated septithiophene derivative bearing methyl groups (10).

Disilylated oligothiophene derivative bearing acceptor moiety (12).
The reaction was performed according to example procedure A. The reaction was carried out with

Disilylated oligothiophene derivative bearing acceptor moiety (14).
The reaction was performed according to example procedure B. The reaction was carried out with 37.5 mg (0.06 mmol) of 13 and 192.7 mg (0.27 mmol) of 2g. 12 was obtained as a dark purple solid (59.6 mg, 0.037 mmol, 61% yield) after purification by silica-gel column chromatography (SiO 2 , CH 2 Cl 2 /hexane, 0:100-30:70) and recycle preparative GPC. We observed that 1 H NMR spectrum changes depending on the concentration of the sample, probably because of its aggregation. We carried out 1 H NMR analysis at ca. 3×10 -3 M and 13 C spectrum at ca. mg, 0.009 mmol), CsF (97.7 mg, 0.64 mmol) were placed in an oven-dried reaction vial. After the vial was sealed with a screw cap containing a Teflon-coated rubber septum, the vial was connected to a vacuum/nitrogen manifold through a needle. It was evacuated and then backfilled with nitrogen. This cycle was repeated three times. After toluene (1.0 mL) was added into the vial through the rubber septum. Then H2O (13 μL, 7.4 equiv) was added to the mixture at 120 °C using an oil bath. After 24 hours, the mixture was filtration with CH 2 Cl 2 to remove the starting material and inorganic salts. The crude mixture was then purified by flash column chromatography (SiO2, typically DCM/hexane, typically 0-10:90) and recycling preparative GPC to give the corresponding coupling product 3d as an orange solid (65.4 mg, 0.050 mmol, 50% yield).

Investugations of the effect of ball milling
To clearfy the effect of ball-milling process, we conducted some additional control experiments.
The reaction between 1 and 2d was carried out in a jar without milling while applying a heat gun, resulted in no product formation. In addition, we also checked the reaction in a test tube with stirring bar (1020 rpm) and 3d was obtained in 33% yield, which was much lower than that of the ball-milling conditions (79%). These results suggest that the ball milling process is essential to achieve the high reaction efficiency.

The use of trimethylsilyl group (TMS) as a solubilizing group
The cross-coupling reaction between 1 and 2-boryl thiophene bearing a TMS group was investigated.
The reaction proceeded to give the corresponding product, however, the solubility of the product is very low and the purification by column chromatography was sluggish. The product was obtained in only 12% yield. This result suggests that the use of a silyl group with long alkyl chains as a solubilizing group is essential for this strategy.

Thermography Observation for Reaction Temperature
The temperature inside the milling jar after the solid-state coupling reactions was confirmed by observation with a thermography camera immediately after opening the milling jar ( Figures S6 and   S7). When the preset temperature of the heat gun was 250 °C for a 1.5 mL stainless jar and 5 mm ball (30 Hz, 30 min), the internal temperature was determined to be 122.8 °C ( Figure S6). On the other hand, when a 5 mL stainless jar and 10 mm ball (25 Hz, 90 min) were used, the internal temperature was determined to be 121.7 °C ( Figure S7).